Crystalline polymorphs of a 1-thiazol-2-yl-pyrazole-5-carboxylic acid derivative
Inventors
Cooper, Alan • Wu, Zheqiong • Kuang, Shanming
Assignees
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Publication Number
US-12378234-B2
Publication Date
2025-08-05
Expiration Date
Abstract
This disclosure relates generally to crystalline polymorphs of a thiazolylpyrazole derivative, pharmaceutical compositions comprising them, and methods of using the crystalline polymorphs and their compositions.
Core Innovation
The invention relates to crystalline polymorphs of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (Compound 1), including polymorph forms and optionally polymorphs in the form of a salt and/or a hydrate or solvate. The solid forms are characterized by XRPD peak sets reported with 2θ±0.1° peak positions, and by thermal characterization including DSC endotherms.
The crystalline forms are further characterized by FTIR peaks, thermal/hygroscopic stability, and dynamic vapor sorption. Variants include hydrate/solvate forms and salt forms, including potassium, sodium, magnesium, urea, and L-arginine or L-proline derivative forms. Additional physical characterization includes solubility in water and biorelevant media such as SGF, FaSSIF, and FeSSIF, including form stability and in-conversion.
The invention also provides therapeutic rationale for use of Compound 1 solid forms for cancer treatment via cell cycle arrest at G0/G1, apoptosis/cytotoxicity, and inhibition of glutathione synthesis, connected to hyperproliferative disorders. Pharmaceutical compositions comprising the crystalline polymorph and pharmaceutically acceptable excipients, diluents, or carriers are described, with broad cancer indications including KRAS-mutant solid tumors and hematopoietic cancers.
Claims Coverage
The claims include independent protection for crystalline polymorphs of Compound 1, including optional salt and hydrate/solvate forms, as well as formulations and a therapeutic use. The coverage identifies multiple inventive features anchored by XRPD peak sets and quantified diffraction-peak inclusion rules, and extends to pharmaceutical compositions and treating hyperproliferative disorders with an effective amount.
Crystalline polymorph with optional salt and hydrate/solvate
A crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a salt thereof and/or a hydrate or solvate thereof.
Crystalline polymorph defined by XRPD peak-set rule
A crystalline polymorph is characterized by an XRPD pattern containing four or more peaks at specified 2θ values (±0.1 degrees).
Crystalline polymorph defined by XRPD peaks selected from alternative sets
A crystalline polymorph is defined by having an XRPD pattern that includes at least four specified diffraction peaks with given 2θ values within ±0.1 degrees, selected from one of two alternative peak sets.
Pharmaceutical composition with pharmaceutically acceptable excipient/carrier
A pharmaceutical composition that includes the crystalline polymorph along with a pharmaceutically acceptable excipient, diluent, or carrier.
Treating hyperproliferative disorder by administering an effective amount
A method for treating a hyperproliferative disorder by administering an effective amount of a crystalline polymorph.
Overall, the claims cover crystalline polymorphs of Compound 1 with optional salt and hydrate/solvate forms, where identity is supported by XRPD peak sets using a quantified four-or-more peak requirement within 2θ±0.1°. The coverage further extends to pharmaceutical compositions containing pharmaceutically acceptable excipients/carriers and to methods for treating hyperproliferative disorders by administering an effective amount.
Stated Advantages
Crystalline forms characterized by XRPD peak sets, DSC endotherms, and FTIR peaks.
Thermal/hygroscopic stability is characterized.
Solubility in water and biorelevant media (SGF, FaSSIF, FeSSIF) is addressed, including form stability and in-conversion.
Therapeutic rationale supports cancer treatment including cell cycle arrest at G0/G1, apoptosis/cytotoxicity, and inhibition of glutathione synthesis.
Documented Applications
Treatment of hyperproliferative disorders by administering an effective amount of the crystalline polymorph.
Cancer treatment, including KRAS-mutant solid tumors, and hematopoietic cancers.
Pharmaceutical compositions comprising the crystalline polymorph and pharmaceutically acceptable excipients, diluents, or carriers for therapeutic use.
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